CICM ASM 2016 – a quick summary

CICM ASM 2016

– a quick summary

By Pierre Janin

[Disclaimer: Pierre wrote this to update those of us at RNSH who couldn’t make it. I thought it is too good not to share while current & Pierre agreed; this is not an official or comprehensive summary, just one attendees account]

Update on resuscitation

The Victorian registry for OHCA reports ~50% survival and discharge home for VF arrest and ROSC on scene. A major determinant is the bystander witnessed factor. The non-VF arrest carry a much worse outcome; unwitnessed asystolic arrest is ~0% survival rate.

There are limited changes to the ALS algorithm. Ultrasound imaging in PEA arrest is recommended. For traumatic cardiac arrest, chest compression is somehow de-emphasized and focus is placed on thoracostomy (first line intervention in many centres), breathing and transfusion.

There are extrapolated data about potential toxicity of hyperoxia. Comparison of O2 vs Air in STEMI patients shows lower cardiac enzymes in the low oxygen group. The data for the brain is unclear; hyperoxia on first ABG (hospital arrival) compared to normoxia leads to worse outcomes.

There is an ongoing trial (EXACT study) with NHMRC grant. The pCO2 target is also questioned; the NSE level was significantly decreased in the group with mild hypercapnia in a phase 2 study. The TTMH study is a phase 3 study that has been submitted for NHMRC support. Observational data suggest an association between higher SBP (120 mmHg) on hospital arrival and better outcome.

Temperature control post-TTM trial has become problematic; maintaining 36 is much more difficult compared to 33 because of shivering. Apparently this is one of the reason why 33 was chosen in the first place (no shivering). The effect on outcome of slightly higher temperature (above 36) is unknown. The CHEER trial for refractory arrest (pilot study) used peri-arrest hypothermia (not post-arrest) showed substantial survival rates. The survivors all went home. For patients who cannot receive ECMO, there are reports of using Esmolol and Isoprenaline in refractory arrest situations. Mechanical CPR is being increasingly introduced in the ambulance in order to bring the patient to the Cath Lab while receiving CPR.

Regarding testing and prognostication, absent SSEP is highly reliable but there are exceptional case reports of unexpected survival. A “bad” MRI seems associated with 10% survival?

Antimicrobial use in the critically ill patients

The original data on time to effective antibiotics in the setting of refractory hypotension is about a decade old. A number of other data showed similar results (surviving sepsis data, Spanish data), including the association between delayed antibiotics and increased ICU length of stay.

However, a meta-analysis could not find the same result (cut-off was within 3h or not); the conclusion suggested that more data is needed to define what an adequate timeframe is.

Many studies are observational data without RCT, therefore including patients with multiple diagnosis, including non-infective problems. There are well recognised regions with pan-resistant infections outbreak. Initial choice recommendation depends on the local population and should be directed by an ID team.

Combination therapy is often used in empirical choice to achieve adequate GNR cover in this setting; this is not kept for more than 3 days typically. Dosing is an important problem in ICU patients. Regarding dosing there is documented association between outcome and achieving a PK/PD target.

The loading dose for vancomycin is based on total body weight and likely around 30-35 mg/Kg. The maintenance infusion is around 30 mg/Kg/day; this should be adjusted depending on the renal function. Creatinine clearance is an independent factor that will affect achievement of the target for many antibiotics, including B-lactams. Interestingly, 600mg BD for Linezolid may not be sufficient for patients on RRT. Many normograms are developed for RRT and individual antibiotics. At this stage, dosing during ECMO should be the same as the non-ECMO dosing. A systematic review suggest a mortality benefit in patients receiving continuous infusion antibiotics.

The BLING (BLactam INfusion Group) is looking at the role of continuous infusions. Unexpectedly, the BLING-II study (large RCT) showed no benefit in terms of survival and clinical cure. This could be explained by the low number of patients on RRT, the low incidence of resistant pathogens, and the low proportion of microbiological confirmation of infection. The BLISS study included patients with more resistant pathogens. Combined data from BLING and BLISS showed a mortality reduction in the continuous infusions groups. Overall, it seems unlikely that continuous infusion will be beneficial to a large cohort of patients; however, there may be a subgroup where it could be interesting, in particular patients with difficult to treat infections.

Regarding TDM, there is data showing that it can help improving antibiotic exposure, but there is no data available to show an improved outcome. There is numerous data showing that short courses of antibiotics are safe and adequate in multiple clinical situation, including VAP, pyelonephritis, cellulitis, … For bacteraemia, the data is less clear.

Information about the role of dosing for the prevention of resistance is arising. For example, 8h dosing of Tazocin seems insufficient to achieve killing of Pseudomonas in patients with normal renal function.

Non Invasive Ventilation

There is good data on the benefit in COPD compared to intubation, in terms of mortality.

APO is also well recognised. Situations with unproven benefit are palliative situations, cystic fibrosis. The benefit is questionable in ARDS, hypoxic failure, and non-immunosuppressed pneumonia. This is likely secondary to the need of continuous application to obtain the benefit (recruitment).

There is no meaningful data in asthma. It is also a useful modality in weaning. Airborne infections is regarded as a relative contraindication (experience from SARS in Hong Kong).

There are full helmets with filters that provide no spreading air jet during exsufflation. A problem during NIV for hypoxic respiratory failure is the large negative intra-pleural pressure and the large tidal volumes, with potential harm in terms of lung injury.

A low TV seems virtually impossible with NIV in some patients. Tolerating a high RR may be relevant. Mask tolerance is fundamentally important.

Ideally, NIV should start at low pressures with the patient holding the mask himself. Titration should be frequent.

Anatomical variations mandates the availability of a large number of different types of mask and sizes. Nasal masks have the benefit of flushing the upper airway and reducing the dead space. Full helmet masks are becoming more popular and eliminate the problem of skin injuries. Recent data suggest a potential mortality benefit?

There is little data on the use of sedation during NIV. Chloral hydrate is useful in children. Dexmedetomidine is one of many options.

Failure is usually argued if no improvement is seen within 1-2h; this can be extended to ~6h in COPD patients.

NAVA is a non-pneumatic triggering method that could solve some issues in NIV, especially in dynamic hyperinflation situations.

High flow nasal cannula is popular as they are very comfortable.

They become preferred to NIV in many situation of hypoxic respiratory failures. Some data suggest a better outcome. They are also useful in palliative situations. NIV can be viewed as a very invasive intervention.

This has implications in the context of end-of-life situation.

Echocardiography

Speckle tracking is the growing technical improvement in echo. It has considerable potential but remains a research tool today. The lack of compatibility among vendors is an unresolved issue.

Interestingly it can also allow to track ventricular motion during diastole, which is of high clinical relevance in many clinical situations.

Strain is an important technique in this family. Global Longitudinal Strain is one of the most validated technique, and seems more sensitive than EF in many scenarios including septic cardiomyopathy.

Torsion (twisting) is an important contributor to stroke volume (~40%), as well as diastolic function. This is not well assessed using traditional EF, but can be studied with Strain imaging.

TDI (tissue Doppler) has been a major advancement and allows estimation of pressures.

But there is an important problem related to the fact that the technique is not well standardised across studies and machines. The mid-portion of the spectral TDI trace should be used in critical care, especially for research.

Ventriculo-arterial hemodynamic coupling can be assessed using echo and is promising, in sepsis for example.

Contrast echo is the second major technical improvement potentially relevant to ICU.

New contrast solutions have very small size particles, much smaller than red cells; it will therefore not be up taken into the lung and can be used to visualize the LV.

It can also provide a dynamic coronary perfusion study (need special equipment).

3D has been a rather disappointing technique in ICU, and remains remote from everyday application in critical care. It requires expensive probes and echo machine.

Currently only 25% of units offer in-house training, while 60% offer no training at all. Training is a question that is recognised by all ICU societies around the world.

This is a problem shared by other Specialties, including Obstetrics for example.

The ASUM CCPU has been a pioneer in defining Basic level echo. The advanced level typically refers to the DDU and the EDEC European Diploma). The EDEC is much less demanding than the DDU.

The system that has been put in place within a unit is the core question for incorporating echo into clinical practice. This includes the problem of archiving, reporting, maintenance and quality control.

Mind-machine interface in ICU

Medical errors remains one of the leading cause of death in the USA.

Reducing errors can be achieved by reducing the steps or improving reliability of each steps.

For example, a blood transfusion implies ~25 steps.

Automation and computation provides a solution. But the number of data to be reviewed in daily clinical practice is impossible for a single human brain. A poorly implemented EMR system can have negative impact on outcomes, including mortality. It can also contribute to Doctor’s disillusion and subsequent impaired empathy for the patient.

The computer of the future is an invisible computer that will facilitate medical task, using human factors engineering and improved understanding of clinical practice.

The goal is to extract high value data and package them into a highly meaningful information for the receiver (information lensing).

It needs to be near-real time, filtered for alerts, and embedded into the workflow.

For example the alarms should be set up to trigger only if the clinicians’ intervention (current ventilation setting …) does not match appropriately the vital sign problem.

Use and misuse of technology to improve CCM

The apparition of the mechanical ventilator led to the need to cluster all sick patients in a single unit. Telemetry was another major enabling technology, which helped to drastically reduce mortality after AMI.

ICU overall has been built around the development of technology.

With this comes an enormous amount of data. Technology has improved capability (definitely), efficiency (probably), but the answer for quality at a population level is much less clear.

Technology overall rarely improves health on the whole (contrary to smoking cessation for example…). Technology is adopted for multiple reasons.

Necessity, but also technological determinism (technology created its own demand – the use because it is available), and the planned obsolescence (refers to the manufacturers’ strategy to implement innovation gradually).

The problem is overall increase in cost without increase in quality. Technology can reduce efficiency because of the amount of data it produces, and can harm interpersonal relationships. Interestingly, adoption of a new technology is comparable to the sequential steps of grieving.

Mindfulness for the Intensivist

Mindfulness is a way of being aware of the present more fully, and a sense of being with the experience with more acceptance and gentleness.

This relates to a practice of curiosity.

Self-compassion physiology links to more sooth performance, and better learning.

On the opposite, self-esteem is related to narcissism, lack of empathy and prone to depression. Mutli-tasking is more like flickering.

Risk and sleep deprivation

Fatigue is an inevitable consequence of the workplace.

Sleep loss has implications to patient safety. Fatigue effect can be compared to moderate alcohol intoxication in terms of performance impairment.

But the lack of resource can be an issue that limits the possibility for reducing fatigue. A tired worker is preferable than no doctor at all. The question is then about strategies to deal with fatigue (“fatigue-proofing”).

It has been suggested that changes to working time arrangements have limited benefits in reducing the likelihood of adverse events, and it may be better to increase the resilience of workers to fatigue-related errors.

Multiple systems have been developed by multiple industries (airlines, trucks …).

In critical care, double-checking medication doses, ensuring proper awakening during a night call for example, can be implemented. This is “re-proceduralising” the operational environment; this implies a good understanding of the meta-structure of the work environment.

Strategic use of simulation

Education and training is a strategy that is one of the least effective to improve care quality, but comes at the neck of the funnel after all other components of the system have been implemented. But poorly designed training programs will waste time and resources without changing outcomes.

The 3 main uses of simulation in ICU:

discovery simulation (driven by the need to find a new way)

diagnostic simulation (driven by need to improve existing standards)

repeated simulation for excellence (driven by need to reduce variability and achieve best standards).

Simulation shines a light on how people work in a system.

It is part of a quality improvement plan.

Identifying the most common adverse complication, new equipment, patient feedback, can help designing targeted simulation training.

Advanced imaging in TBI

The long term burden after TBI may be related to medically treated conditions as opposed to surgical injuries.

CT may be an inadequate modality to recognise more subtle forms of injury, especially since axonal injury is a major driver of outcome.

Even at later stages, CT correlates poorly with cognitive and behavioral deficits.

CT provides very limited information about pathophysiology and is a poor biomarker for novel interventions targeted at key physiological processes. Functional imaging (advanced MRI and PET) may provide a way to individualise targets, for example identifying patient where aggressive CPP treatment will provide benefit.

It can provide remarkable insights into the mechanism of secondary injury. It allows to dissect the contribution of classical ischaemia, diffusion hypoxia, and possible mitochondrial dysfunction.

Interestingly, one can demonstrate that hyperventilation produces hypoperfusion.

Specific tracers can be used to demonstrate the mismatch between perfusion and hypoxia (tracer binding to hypoxic tissue). Mitochondrial dysfunction (imaging with specific tracer) is another situation.

Hyperoxia could be a treatment option then.

Prevention of delirium, and the DahLIA trial

Association of inattention, change in cognition (perceptual disturbance), and fluctuation over time. Can be hyper or hypoactive. A same patient can oscillate between the 2 types.

The effect of Benzodiazepines may be present in continuous infusion administration only. Noise reduction can provide moderate reduction in Delirium.

Other proven interventions include exposure to daylight, early mobilization. In high risk patents, prophylactic Haloperidol has no benefit.

Quetiapine has shown benefit for the treatment of delirium.

However there is no support for anti-psychotics in general, in terms of improved outcomes. Evidence exist for Dexmedetomidine to reduce the incidence of delirium.

DahLIA trialed Dexmedetomidine as a treatment for established delirium, for patients who cannot be extubated because of ongoing delirium. 74 patients were recruited instead of the 96 target. It was a very slow trial, terminated when the company withdrew support. The primary outcome was ventilator free hours in the first 7 days. A significant difference was shown. The intervention group was liberated quicker from ventilation; delirium scores were less. ICU and hospital length of stay, and mortality were not significantly different (small study population).

Prognostication after cardiac arrest

The prognostication aspect is included in the ANZCOR guideline. It states that clinical examination early should not be used to prognosticate.

The use of other modalities and waiting at least 72h is suggested.

Absent pupillary responses is a recommended predictor, but relying on a poor motor score should be discouraged.

Myoclonus alone is unreliable, but status myoclonus is a good predictor. However there is no good definition of status myoclonus at this stage. Status myoclonus, status epilepticus, and MSE are poorly understood.

The use of N20 is reliable, with low cost and easy to use equipment.

Absence of EEG reactivity at 72h is reliable too. The BIS has a high false positive rate.

NSE is associated with a lot of unanswered questions (cut-off …). Specific sequences in MRI may have promising results for the future.

Patients with good neurological outcome usually wake within 5 days after the arrest.

Modern stroke therapy

The world of stroke practice has changed because of the concept of ischaemic penumbra.

The penumbra is the area doomed to die unless perfusion is restored rapidly.

In rats, infarction occurs within 10 min after vessel occlusion and extends over the next hours. Similar process can be seen in the human brain. It is all about reperfusion and how quickly it happens. The benefit of thrombolysis declines over time. The benefits roughly halves every 90 min and is questionable after 4.5h.

Therefore exist the concept of “door to needle time”. Some centres have achieved times ~20min.

History and decision is made before the patient arrives and thrombolysis is administered in the CT scanner. However, not everyone benefits from thrombolysis. Patient with large vessel occlusion do worse.

The clot is bigger and more resistant to treatment, and the brain dies faster. In severe stroke the benefit of thrombolysis is to double favorable outcomes, but this means going from 5 to 10% favourable outcomes only. There are numerous previous failed endovascular trials. Retrospectively, the failure was expected because of poor patient selection (no proof of occlusion required), reperfusion occurred too late and the reperfusion rate too low.

This was also confounded by off-label treatment in the USA, where there was a lucrative disincentive to enroll patient in the trial. An import Dutch trial published in NEJM brought useful information. No off-label use. A positive result was found, despite a later and low reperfusion rate. This led to premature cessation of 3 other trials because of loss of equipoise.

All 3 trials were presented later and were strongly positive. This was a major change in the world of stroke.

The NNT to achieve near cure was around 4 in all this trials, with also a suggestion of mortality benefit. The trials were heterogeneous in terms of speed and rate of reperfusion; pooled together this showed no real harm and strong effectiveness, in nearly all populations. The few caveats may relate to distal MCA occlusion, and loss of ischemia on the CT.

The trial who in which thrombolysis was done the fastest had the greatest benefit (EXTEND IA vs MR RESCUE).

Other lessons are that early clot dissolution is rare (10%).

The highest reperfusion rate used stent retrievers (Solitaire).

Elderly patients should not be excluded as they show the greatest benefit.

This leads to a demand of radical redesign of stroke care in Australia.

It is estimated that about 10% of ischaemic strokes will be eligible for this treatment. For example this translates into about 1 per day in Melbourne.

Treatment after AVM resection

The Spetzler-Martin system is a grading system to estimate the risk of surgery.

It takes into account size, location, deep venous drainage.

Delayed haemorrhage after surgery is not uncommon.

Reasons may relate to altered auto-regulation around the AVM (normal perfusion pressure breakthrough).

You can demonstrate on rats with AV fistula that CBF is initially low, then that the CBF is increased after occlusion of the fistula.

Experimentally, with high CO2 you can cause a breakthrough.

You can see changes in the capillary, such as loss of the foot processes.

Another mechanism is linked to the rapid pressure increase in surrounding capillary after AVM occlusion. The CBF is influenced by the AVM.

The wall shear stress is proportional to the flow and inversely proportional to r3.

This stress needs to be tightly controlled. NO and Endothelin are mediators that control the immediate response, but there is a sustained effect.

After a few days, surrounding vessels are highly pulsatile and will remodel.

Narrowing occurs; day 0 to day 1 there is constriction while around day7 arteries start to reopen again and no longer need to constrict to protect circulation. The proposed protocol by this speaker is to maintain CPP>50 and MAP<70. Thiopentone is used if CPP target cannot be met.

For simple AVM (cf Spetzler score) the rate of delayed haemorrhage is very low and the BP protocol is not useful. The group of more complex AVMs (Spetzler 4 and 5) would appear to benefit the most.

The BP protocol should be applied until remodeling has occurred (~8 days).

Update on SAH

The mortality is high, when patient who don’t reach hospital are included.

The modern CT has a diagnostic sensitivity of nearly 100%, especially if the CT is done within 6h.

Grading is WFNS clinical and Fisher for radiological.

It does not adequately take into account the location, which can be highly relevant.

The SAH volume per centre is a driver for mortality but also for functional outcomes.

DSA remains a gold standard. But modern CT (64 rows) have become very good and are capable of diagnosing small aneurysms. Sensitivity and specificity is now very high.

For treatment, the ISAT trial compared surgery with INR. A recent study from the same group showed a significant risk of re-bleeding with coiling when patients are followed-up for many years. The rate is still very low. However the odds ratio for disability remain in favour of INR.

Those concepts may be relevant for very young patients.

ISAT II is an RCT that will follow patients over 12 years. The benefit of very early treatment of aneurysm is documented, and of particular benefit for low grade SAH.

Adjunct therapy such as Tranexamic Acid increases the risk of cerebral ischemia without changing mortality or functional outcome. A benefit may exist if administered ultra-early, until clipping is performed (ongoing study).

Delayed ischemic deficit (DID) is found in about 25% of patients while vasospasm is described in 50-60% patients. This gives insight on the role of preserved auto-regulation. There is no difference between INR and clipping.

There are well described risk factors for DID, including chronic HTN, fever (unmasks DID?), volume depletion… The problem is that many drugs who reduce vasospasm fail to reduce DID and improve outcome.

There are other mechanisms that could explain DID, including spreading depolarisation, abnormal auto-regulation, micro-thrombi, abnormal BBB… There is a recent interest in PDEI (Milrinone).

Transcranial Doppler is good, with very good negative predictive value. CT-perfusion can be used for diagnosis, but not prediction of DID. The time to peak is probably the most specific parameter. CT-perfusion could help decide when it is safe to wean pressors, especially in high risk patients.

Crowdsourcing to inform clinical care in the ICU

Crowdsourcing is a novel approach to complex problems solving and may represent one solution. Crowdsourcing puts the problem to the online public community. It can be applied to data processing, and has been used successfully in various non-medical fields.

Multiple websites exist. It can also be applied to funding (crowd funding) to develop new businesses for example. For ICU, it can help in multiple areas. For example it can assist prescription, or could identify missed practices in daily clinical management. It is putting a wide eye, and watch, on bedside practice.

The pitfalls and benefit of big data

EMR analytics have fallen short of its promise. There are vendor barriers, lack of common standardised data, problem of garbage … Medical data is very challenging for multiple reasons (interpretation, missing data …).

Large datasets introduce problems and biases that are substituted to other problems found in small data. History has examples of major harm from big data analysis, including Ford tragedy, the Vietnam War.

There is a high risk of false discoveries in Medicine. One of the real power of data is collecting accurate family history. This can be obtained using crowdsourcing. Data analysis can be used to monitor resource and activity, recognising clinical syndrome and calculate the incidence, understanding trends.

Future of cardiac support

Current survival for heart transplant is ~60% at 10 years. One of the benchmark is ~80% survival at 1 year.

The main problem is unmet demand.

Ways to answer this issue are multiple: – Extending donor criteria, like using older donor (late 60s), “backtable” donor heart surgery, HCV positive donors – Extending donor ischemic time – DCD heart donation (Transmedic system, which is complex and expensive). – Xenotransplantation: this is no longer out of scope (reports in animals exist, with a prediction of kidney transplant in human within 2 years).

VADs used to have a heavy burden of problems, but continuous flow devices have become long term options. Problems are multiple, including bleeding (acquired Von Willebrand), thrombosis, lack of pulsatility (role in the development of AV fistula?), infection (via the drive line, untreatable unless a transplant is performed), RV failure (20-30% of RV ejection is due to LV function), worsening AR (progression is predictable, driven by the jet of the outflow line and the suctioning from the inflow).

At 1 year, 12% have died, 50% survive, and others have been transplanted.

We are now talking of equivalent survival between heart transplant and LVADs.

Mechanical supports will likely emerge as a major solution for end stage heart failure. Future developments should include devices with transcutaneous powering, and bi-ventricular support systems.

EEG and SSEPs

ICU is electrically hostile for EEG. For EEG to be useful, it is important that it is not simplified.

One of the problem of BIS monitoring is that the electrode is placed where most artefacts are present.

Clinical context is essential for interpretation.

Continuous EEG is sometimes needed. But there is a problem about who reads the data.

Some smart machines exist and can be useful for the reading.

Regarding the use of EEG for prognosis, the aetiology drives the prognosis much more than the EEG pattern itself.

Triphasic waves are typical of metabolic problems, and are enhanced with stimulation. PLEDs are seen in acute and subacute focal insults of any aetiology.

It is different from status, but is a peri-ictal phenomenon that can explode into seizure. SIRPIDs are very common and are very different from seizure.

They are triggered by stimulus. Studies show that if EEG did not pick up seizure during a 30 min study, then the chance of finding seizure on continuous EEG is less than 5%.

There is also a risk with cEEG to treat benign forms and produce harm.

This has been suggested in previous studies. SSEPs are in the magnitude of micro-volts in sensitivities. About 10% of units cannot record SEPs because of technical factors.

Patients with bilateral absence of N20 have a poor prognosis but they typically also have terrible EEG pattern. However, present N20 correlates with survival in only 30% patients.

ICU bed demand

Many disease in ICU are disease of the elderly and therefore will increase.

Data suggest that there is harm related to delayed admission to ICU, and admission to strained ICU. But building more ICU beds carries many problems. Supply induced demand exist for ICU beds. Increasing ICU beds leads to admission of less sick patients.

Data suggest that mortality is not affected, but costs are markedly increased.

This is because most ICU costs are fixed costs.

The goal is to increase responsiveness of the hospital system. Steps involve examining processes, identifying areas of waste (management based on industrial engineering concepts – Toyota TPS). However, Medicine is different from automotive industry.

This remains a process to improve efficiency, but not quality.

TBI management

TBI is an area where EBM is very limited.

There is little way to measure what we are doing in Neuro Critical Care.

Overall we don’t really know how to treat TBI, and a lot of what we do is based on associations.

ICP is one the biggest controversies. There is no data to prove that treating based on ICP improves outcome. Results from DECRA, Eurotherm, previous studies on hyperventilation, all suggest potential harm. Most ICP protocols combine interventions which all are on their own controversies.

The surrogates outcomes used in everyday practice are not necessarily pushing into the right direction. We need to measure relevant outcomes.

Compared to 30 years old data, the current outcome results have not really improved. One major problem is the underestimation of significant disabling outcomes among patients who are classified as survivors and as a good outcome.

Temperature control in TBI

Temperature control is pounded by significant uncertainty.

There is no recommendation in the TBI guidelines.

Temperature elevation in an injured tissue is part of normal tissue repair (inflammation).

Hypothermia and normothermia are beneficial in diverse animal models of brain injury. But overall observations in TBI suggest that temperature below 36 or above 38 may be harmful.

Clinical trials suggest no benefit from induced hypothermia, for patient-centered outcome, and often suggest harm compared to normothermia.

A logical hypothesis would be to target temperature around 36-38.

An Australian survey showed that patients commonly reach the 36-38 range. This is often with using interventions to control temperature. Paracetamol tends to achieve a temperature difference around 0.3.

An Italian group is reporting routine use Diclofenac (upcoming publication).

TBI as a chronic progressive disease

Data suggest that TBI is a progressive disease.

This is shown by steeper curve of survival compared to control. Patients after TBI have a higher risk life.

Multiple disorders are described, including sleep disorder, depression, hypopituitarism, psychosis… Traumatic chronic encephalopathy is a condition described in football players.

There are stages defined for the condition. It is hypothesized that TBI may be the trigger of crossing to the “pathology” stage in predisposed patients for dementia.

Genetic predisposition is probably a significant driver of outcome.

Brain volume is shown to be shrinking more rapidly over time. This is suggested from imaging and autopsies.

Literature suggest an increased risk on neurodegenerative disorders, with more frequent diagnosis such as dementia (Alzheimer’s, in male patients).

Some of this relates to the concept of cognitive reserve. Increased amyloid deposition can be demonstrated, in a similar pattern compared to Alzheimer’s. There are many more protein types that show deposition (in the spectrum of Parkinson, Lewy bodies, Fronto-temporal dementia). Amyloid can now be imaged in TBI patients (C11-labelled compound B). There is increasing evidence of amyloid deposition.

The trajectory of patients after TBI can eventually be followed. These protein deposits are associated with cerebral inflammation (neuro-inflammation). This can be shown with PET and microglia activation. There is an association between inflammation and white matter loss. This inflammation can be observed in TBI patients for years after the initial injury.

There seems to be an association between the amount of inflammation and the functional outcome. The loss of white matter tracts continue after the acute phase during years, and this seems to correlate with outcome. A proportion of patients after TBI will develop an adaptive immune response to brain proteins. Boosting T-cell immunity may offer a therapeutic approach in neuro-degeneration (adaptive response may contribute to repair). The question of neural vaccine is raised. Trials for therapies will be difficult as very long follow-ups are required.